J Chin Med Assoc

Original Article

The effect of aspirin on preeclampsia,

intrauterine growth restriction and preterm
delivery among healthy pregnancies with
a history of preeclampsia
Nazanin Abdia,b, Afsane Rozrokhc, Azin Alavib, Shahram Zared, Homeira Vafaeia, Nasrin Asadia,
Maryam Kasraeiana, Kamran Hessamia,e,*
a
Maternal-Fetal Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; bFertility and Infertility Research
Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; cStudent Research Committee, Hormozgan University of
Medical Sciences, Bandar Abbas, Iran; dEpidemiology Department, Hormozgan University of Medical Sciences, Bandar Abbas, Iran;
e
Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract
Background: Due to the significance of preeclampsia (PE) and its adverse outcomes in the health of both mother and newborn,
the present study was carried out to investigate the effect of aspirin on preventing the occurrence of PE, intrauterine growth restric-
tion (IUGR), and preterm delivery in women with a previous history of PE.
Methods: The present clinical trial was conducted on 90 pregnant women with a previous history of PE referred to the Khalij Fars
Hospital in Bandar Abbas, Hormozgan Province Iran from April 2017 to August 2018. The subjects of the study were randomly
assigned into two groups of intervention and control to receive either 80 mg of aspirin or placebo daily during the pregnancy.
Patients’ information was obtained and recorded upon entering the study, follow-up visits, and childbirth.
Results: Among participants who entered the clinical trial, 86 patients (95.6%) completed the study. During the pregnancy, systolic
blood pressure increased by 8.25 ± 14.83 and 19.06 ± 18.33 mmHg in aspirin and placebo groups, respectively (p = 0.001). Also,
the same happened with diastolic blood pressure (6.12 ± 11.46 vs 13.48 ± 13.95 mmHg, p = 0.010). The rate of PE was equal to
27 (62.8%) and 38 (88.4%) in the aspirin and placebo groups, respectively (aOR = 0.23, p = 0.013). In the aspirin group, the rate
of IUGR was equal to 27.9% compared with 25.6% of newborns in the control group (aOR = 1.18, p = 0.750). Similarly, there was
no significant difference in the rate of preterm delivery between the two groups (p = 0.061).
Conclusion: The findings of the present study conducted exclusively on women with previous documented PE revealed that tak-
ing aspirin may have a preventive effect on PE in the current pregnancy.
Keywords: Aspirin; Intrauterine growth restriction; Preeclampsia; Preterm delivery

1. INTRODUCTION Several explanations have been proposed for development of

Preeclampsia (PE), as one of the main causes of maternal and
perinatal morbidity and mortality, complicates about 2% to 8%
of all pregnancies worldwide.1 PE is a unique systemic disorder
of pregnancy that is characterized by elevated blood pressure
and proteinuria or its equivalents after 20 weeks of gestation.2
PE alters the placental blood flow and triggers vascular dis-
orders in different organs of the mother’s and fetus’s body.3,4
*Address correspondence. Dr. Kamran Hessami, Maternal-Fetal Medicine
(Perinatology) Research Center, Shiraz University of Medical Sciences, Hafez
Hospital, Chamran Ave., Shiraz, Iran. E-mail address: hessamikamran@gmail.com
(K. Hessami).
Conflicts of interest: The authors declare that they have no conflicts of interest
related to the subject matter or materials discussed in this article.
Journal of Chinese Medical Association. (2020) 83: 852-857.
Received August 5, 2019; accepted May 12, 2020.
doi: 10.1097/JCMA.0000000000000400.
Copyright © 2020, the Chinese Medical Association. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/)
PE including vascular spasm, vascular endothelial cell damage,
raised platelet activity, and increased coagulation system activ-
ity in small blood vessels.5,6 However, despite extensive research
efforts, the exact pathophysiology of PE is still unknown.7
Delivering the placenta is the only definitive treatment of
PE; but on the other hand, preterm delivery itself can lead to
increased neonatal morbidity and mortality.8 In the past, medi-
cal treatment of PE has been limited to symptomatic relief, pre-
vention of seizure, and prescription of antihypertensive drugs
and agents used for termination of pregnancy.3,9 However, in
recent years, identifying safe and cost-effective interventions for
prevention of various health problems has been the major chal-
lenge in the field of medicine. The use of aspirin for prevention
of PE is among these interventions.10,11 There are contradictory
results in the literature regarding the efficacy of aspirin taken by
high-risk pregnant women. Also, it is hypothesized that intrau-
terine growth restriction (IUGR) and PE share similar patho-
physiology such as abnormal trophoblastic invasion.12,13 In this
regard, a number of studies have reported that taking aspirin
may prevent IUGR as well as PE;13,14 while others did not report
a significant change in IUGR rate after taking aspirin.15

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Original Article. (2020) 83:9
Previous studies on the effect of aspirin for prevention of
PE included pregnant women who were at high risk for PE,
but the exact definition of high risk for PE was different for
each study leading to bias and loss of precision. In some of the
previous studies, chronic medical conditions such as chronic
hypertension,16,17 diabetes mellitus,16,17 abnormal uterine artery
Doppler,15,18 or abnormal serum biomarkers18 in combination
with previous history of PE were used as inclusion criteria for
recruiting the participants to achieve a higher sample size.
While, the novelty and originality of the current research are
that our target population was healthy pregnant women with
a previous history of PE, and the patients with any history of
chronic medical conditions or abnormal Doppler or laboratory
findings in the first trimester of pregnancy were excluded from
the study.
Accordingly, the current study was performed to investigate
the effect of aspirin on preventing the PE, IUGR, and preterm
delivery in pregnant women with a previous history of PE.
2. METHODS
The present randomized clinical trial was conducted on 86
patients referred to the Khalij Fars Hospital in Bandar Abbas,
Hormozgan Province, Iran from April 2017 to August 2018 to
receive their prenatal care. The inclusion criteria were pregnant
women with gestational age of 12 to 15 weeks and a history of
PE in previous pregnancies (at least one previous pregnancy).
The exclusion criteria were multiple gestations, gestational dia-
betes mellitus, chronic medical diseases (eg, hypertension or
diabetes mellitus), smoking, coagulation disorders, abnormal
uterine artery Doppler at ultrasound screening,19 abnormal
serum level of pregnancy-associated plasma protein A (PAPP-A)
at the first-trimester screening,20 allergy to aspirin, and unwill-
ingness to participate in the research.
The study protocol was discussed and approved by the
Medical Ethics Committee of Hormozgan University of Medical
Sciences (HUMS.REC.1396.89), and informed consent was
obtained from each participant after explaining the objectives
of our study. This research was also registered at the Iranian
Registry of Clinical Trials (code: IRCT20181218042033N1).
The patients were randomly divided into two groups accord-
ing to the output table of the Random Allocation software: (1)
intervention group including pregnant women who were at
the gestational age of 12 to 15 weeks and were treated with
80 mg of aspirin orally daily, and (2) control group including
those who received the placebo for the same period of time.
In both groups, the treatment continued until the 36th week
of pregnancy or discontinued earlier as necessary in cases of
preterm delivery. At the first visit, demographic characteristics
such as maternal age, gestational age, and obstetrical history
were obtained from the participants. At each follow-up visit,
patients were evaluated for development of PE by measuring
blood pressure and urine dipsticks. Also, all the participants
underwent ultrasound examination in the third trimester of
pregnancy for the assessment of fetal growth. Finally, birth
weight, type of delivery (cesarean section [C/S] or normal vagi-
nal delivery [NVD]), and newborn’s Apgar scores at the first
and fifth minutes were recorded.
The data were analyzed using SPSS software version18 (SPSS,
Inc., Chicago, IL, USA). Descriptive statistics were reported as
frequency (percentage) and mean (±SD), respectively. A com-
parison was done between the intervention and control groups
using Chi-Square or Mann-Whitney U test and Student’s t test
for categorical and continuous variables, respectively. A mul-
tivariate logistic regression analysis was used to identify (1)
the associations between PAPP-A values measured at late first
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J Chin Med Assoc
trimester and occurrence of PE after adjusting for potential con-
founders and (2) to test the difference in the incidence of PE,
IUGR, and preterm delivery between the aspirin and placebo
groups. Furthermore, Kaplan-Meier survival analysis was used
to estimate the PE, IUGR, and preterm delivery rates during the
pregnancy. A p value of <0.05 was considered as statistically
significant.
3. RESULTS
Among the 100 pregnant women assessed for eligibility, 90
patients were randomly assigned to the aspirin (n = 45) or
placebo groups (n = 45), respectively. Ten participants were
excluded before entering the trial due to previous chronic medi-
cal disease (n = 4), abnormal PAPP-A values (n = 3), abnormal
uterine artery Doppler at the first trimester (n = 1), and history
of allergic reaction to aspirin (n = 2). Two patients from the aspi-
rin group and one patient from the placebo group were lost to
follow-up and one patient from the placebo group discontinued
the intervention due to intrauterine fetal demise (Fig. 1). Table 1
presents a summary of the maternal demographic and obstetri-
cal characteristics. Mean age of the patients in the intervention
group was equal to 29.5 ± 5.5 years old, and in the placebo
group, it was equal to 31.1 ± 6.4 years old, which was not sta-
tistically significant (p = 0.21).
Also, there were no significant differences in the gravidity,
parity, abortion, and dead fetus rate between the study groups
(p > 0.05). At the beginning of the study, mean gestational age
was equal to 13.7 ± 1.3 weeks in the intervention group vs 14.2
± 1.7 weeks in the placebo group (p = 0.13). The rates of NVD
and C/S delivery were similar between the intervention and pla-
cebo groups (p = 0.13).
Mean serum level of PAPP-A multiple of the median (MoM)
in the first trimester was significantly lower in women who
developed PE later in pregnancy compared to those who did
not develop PE (1.14 ± 0.43 vs 1.51 ± 0.45, p value = 0.003).
Table 2 shows the results of multivariate logistic regression. As
depicted in Table 2, adjusted odds ratios (aORs) are given for
PAPP-A MoM values and other maternal risk factors to predict
the PE. Results of the final model of logistic regression (Table 2)
showed that the PAPP-A MoM in the first trimester is signifi-
cantly associated with the occurrence of PE later in pregnancy
(aOR = 15.48, p value = 0.003).
As illustrated in Table 3, the two study groups were compared
in terms of systolic and diastolic blood pressures and heart rate
at the onset and end of the clinical trial. Mean systolic and
diastolic blood pressure at the first visit was similar between
the aspirin and placebo groups (p = 0.261 and p = 0.204). The
systolic blood pressure significantly increased during the study
in the placebo group compared to the aspirin group (19.06 ±
18.33 vs 8.25 ± 14.83, p = 0.001). Also, an elevation in diastolic
blood pressure at the end of the trial was significantly greater in
the placebo group than aspirin group (13.48 ± 13.95 vs 6.12 ±
11.46, p = 0.10). The two study groups showed no significant
differences in the heart rate at the baseline and end of the study
(p = 0.70 and p = 0.95).
The study groups were compared in terms of gestational
age at delivery, birth weight and Apgar scores at first and fifth
minutes and the results revealed no statistically significant
differences between aspirin and placebo groups (p > 0.05)
(Table 4).
Table 5 shows the prevalence of PE, IUGR, and preterm deliv-
ery either in isolated form or in combination. PE was the most
common complication that occurred in both study groups so
that, the prevalence of isolated form of PE was equal to 39.9%
and 60.5% in the aspirin and placebo groups, respectively.
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Abdi et al. J Chin Med Assoc

Fig. 1 CONSORT flowchart of this randomized clinical trial.

Table 1 Table 2
Baseline characteristics of study groups Results of multivariate logistic regression for association
Study groups between pregnancy-associated plasma protein A and
preeclampsia after adjustment for maternal risk factors
Aspirin Placebo p
Variables (n = 43) (n = 43) Variables aOR 95% CI P

Maternal age, years (mean ± SD) 29.5 ± 5.5 31.1 ± 6.4 0.21 Maternal age 0.97 (0.85-1.12) 0.701
Obstetrical history Parity 1.26 (0.44-3.59) 0.662
Gravidity (mean ± SD) 2.8 ± 1.1 3.0 ± 1.2 0.46 SBP 0.96 (0.88-1.05) 0.358
Parity (mean ± SD) 1.3 ± 0.8 1.7 ± 1.1 0.06 DBP 0.99 (0.86-1.14) 0.872
Abortion (mean ± SD) 0.5 ± 0.7 0.4 ± 0.6 0.15 Previous pregnancies with PE 0.16 (0.01-1.82) 0.139
Dead fetus (mean ± SD) 0.2 ± 0.3 0.1 ± 0.2 0.09 Receiving aspirin 0.08 (0.02-0.44) 0.004
Gestational age at the onset of study, 13.7 ± 1.3 14.2 ± 1.7 0.13 PAPP-A 15.48 (2.47-96.87) 0.003
weeks (mean ± SD) aOR = adjusted odds ratio, DBP = diastolic blood pressure, PAPP-A = pregnancy-associated plasma
Number of previous pregnancies 1.1 ± 0.4 1.2 ± 0.5 0.55 protein A, PE = preeclampsia, SBP = systolic blood pressure.
complicated by PE (mean ± SD)
Type of delivery
NVD, n (%) 19 (44.2%) 13 (30.2%) 0.13 pregnancies complicated by PE, a statistically significant
C/S, n (%) 24 (55.8%) 30 (69.8%) reduction was observed in PE rate in the aspirin group com-
C/S = cesarean section, NVD = normal vaginal delivery. pared to the placebo group (aOR = 0.23, p value = 0.013).
However, the results of logistic regression analysis showed
no significant difference in rates of IUGR and preterm deliv-
Additionally, overall prevalence of PE (either in isolated form or ery between the aspirin and placebo groups (p = 0.750 and
in combination with other complications) was equal to 62.8% p = 0.061) (Table 6).
and 88.4% in aspirin and placebo groups, respectively. Figure 2 shows the results of Kaplan-Meier analysis for
After adjusting for maternal variables and clinically rel- PE, IUGR, and preterm delivery. Results of the analysis indi-
evant factors, including age, parity, and number of previous cated that 37.2% of the patients receiving aspirin were not

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Table 3
Study groups compared in terms of vital signs in follow-up and visit to hospital for childbirth
Research group
Aspirin (n = 43) Placebo (n = 43)
Variable Mean SD Mean SD p
SBP at onset of study, mmHg 132.09 15.04 129.88 12.27 0.261
SBP at delivery, mmHg 141.00 18.78 148.95 20.39 0.061
SBP difference during the study period, mmHg 8.25 14.83 19.06 18.33 0.001
DBP at onset of study, mmHg 83.48 9.22 81.39 8.33 0.204
DBP at delivery, mmHg 90.12 13.61 94.88 12.79 0.088
DBP difference during the study period, mmHg 6.12 11.46 13.48 13.95 0.010
Heart rate at onset of study 83.69 3.43 84.04 3.29 0.700
Heart rate at delivery 84.97 3.38 85.03 3.64 0.950
DBP = diastolic blood pressure, mmHg = millimeters of mercury, SBP = systolic blood pressure.

Table 4
Study groups compared in terms of gestational age, birth weight and Apgar of first and fifth minutes
Research group
Variable Aspirin (n = 43) Placebo (n = 43) p
Gestational age (weeks), (mean ± SD) 36.79 ± 2.63 36.30 ± 3.30 0.670
Birth weight (g), (mean ± SD) 2778.60 ± 754.66 2729.06 ± 721.66 0.628
First-minute Apgar, (mean ± SD) 8.60 ± 0.82 8.25 ± 1.57 0.202
Fifth-minute Apgar, (mean ± SD) 9.60 ± 0.76 9.25 ± 1.70 0.357

Table 5 4. DISCUSSION
Frequency of complications of pregnancy among aspirin and Delivering the baby and placenta as soon as possible is the only
placebo groups definitive treatment of PE,8 which can be associated with an
increased risk of preterm birth and its related side effects such as
Aspirin (n = 43) Placebo (n = 43)
a greater need for neonatal intensive care unit admissions, higher
Complication Frequency % Frequency % mortality rate of newborns, etc.21 Review of the literature shows
Uncomplicated 11 25.6 5 11.6 that IUGR, as fetal growth below the 10th percentile appropri-
Preterm delivery 3 7 0 0 ate for gestational age often occurs in association with PE; how-
IUGR 1 2.3 0 0 ever, this finding is maybe due to similar pathologies influencing
PE 15 39.9 26 60.5 the placental blood circulation.22 Concomitant occurrence of PE
IUGR and PE 10 23.3 11 25.6 and IUGR is associated with a worse pregnancy outcome com-
Preterm delivery and PE 2 4.7 1 2.3 pared to either PE or IUGR alone.23
Preterm delivery and IUGR 1 2.3 0 0 Thus, various treatments have been suggested to prevent
the occurrence of IUGR and PE simultaneously including tak-
IUGR = intrauterine growth restriction; PE = preeclampsia.
ing aspirin for those who are at a greater risk especially for PE.
The history of PE in previous pregnancies is among the major
risk factors for the development of PE in the current pregnancy,
so it is considered a useful key for predicting the occurrence of
Table 6 later cases of PE. Preventive treatment with aspirin has been sug-
Rates of preeclampsia, intrauterine growth restriction, and gested recently in previous studies.13
preterm delivery in women treated with aspirin vs placebo In the present study, mean systolic and diastolic blood pres-
Aspirin Placebo aOR sure was not significantly different at the onset of the study.
Variables (n = 43) (n = 43) (95% CI) p Therefore, alteration in blood pressure was measured and aver-
aged to make a between-group comparison in order to evaluate
PE 27 (62.8%) 38 (88.4%) 0.23 (0.07–0.73) 0.013
the effect of intervention on systolic and diastolic blood pres-
IUGR 12 (27.9%) 11 (25.6%) 1.18 (0.44–3.17) 0.750
sure. A significant increase was found in the mean systolic and
Preterm delivery 6 (14%) 1 (2.3%) 9.78 (0.90–105.89) 0.061
diastolic blood pressure in both study groups. However, the
Data presented as number (percentage%). Adjusted odds ratio was adjusted for maternal age, parity, amount of increase in the blood pressure was significantly lower
and number of previous pregnancies complicated by PE. in the intervention group than the control group. So, it could be
IUGR = intrauterine growth restriction, PE = preeclampsia. concluded that aspirin compared to the placebo has a preven-
tive effect on the elevation of blood pressure during pregnancy.
On the other hand, it seems that aspirin is not effective enough
affected with PE during the pregnancy compared to 11.6% in preventing IUGR and preterm delivery. The occurrence rate
of the patients receiving placebo (p = 0.011). However, no of IUGR was found to be 27.9% and 25.6% in the interven-
significant efficacy was observed for aspirin in terms of tion and placebo groups, respectively. Also, the incidence of
reducing the risks of IUGR (p = 0.838) and preterm delivery preterm delivery was equal to 14% and 2.3% in the study
(p = 0.131). groups, respectively. On the other hand, the prevalence of PE

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Abdi et al.
Fig. 2 Results of survival analysis (Kaplan-Meier curve) for three different
complications. A, PE; B, IUGR; and C, preterm delivery. PE = preeclampsia;
IUGR = intrauterine growth restriction.
was estimated to be 62.8% and 88.4% in aspirin and placebo
groups, respectively, so, it can be suggested that the intervention
has a preventive effect on the occurrence of PE.
856
J Chin Med Assoc
Rolink et al,18 showed that the preterm PE rate was equal
to 1.6% and 4.3% in aspirin and placebo groups, respectively.
The difference between the two research groups was statisti-
cally significant (p = 0.004). In their later study, the total num-
ber of women afflicted with PE at ≥37 weeks of gestation was
53 patients (6.6%) in the intervention group while it was 5
patients (7.2%) in the placebo group. However, there are cer-
tain differences between their study and the present research
including the use of higher doses of aspirin (150 vs 80 mg/
day in the present study) and selection of the patients for the
study (so that, in the clinical trial by Rolink et al, 68.5% of
the subjects in the aspirin group and 10.2% of those in the
placebo group had a history of PE in previous pregnancies
while in the present study, all the subjects in both groups had
a history of PE in their prior pregnancies), but the conclusion
regarding the efficacy of aspirin in prevention of PE was the
same in both studies.
In a meta-analysis by Roberge et al,14 the rate of PE, espe-
cially severe PE significantly decreased among the patients
who had consumed aspirin before 16 weeks of gestation.
Also, the rate of IUGR significantly reduced in the patients
who took aspirin than those taking a placebo. An increase in
the dosage of aspirin was shown to be associated with more
favorable outcomes. However, in the above-mentioned meta-
analysis, there was no information regarding previous history
of PE in majority of the patients and the selection criteria
of the patients were not clear enough in most of the studies
included in the review.
In contrast to our study, Odibo et al.8 reported no supporting
data in their clinical trial regarding the effectiveness of aspirin
for preventing PE. A small sample size (n = 30) was among the
limitations of their study as well as a high proportion of partici-
pants who were primigravid with no history of PE.8 However,
despite similarities (such as dosage and onset of aspirin therapy)
between the two studies, our finding regarding the effectiveness
of aspirin was not in line with their study.
Ayala et al.13 and Ebrashy et al.15 found that the rate of PE
differs significantly between aspirin and placebo groups, but
their results regarding the IUGR and preterm delivery rates
were inconsistent. However, in contrast with our clinical trial,
the study participants in most of previous trials were pregnant
women diagnosed with an abnormal Doppler screening of uter-
ine artery or women with other risk factors for development of
PE (not only previous history of PE).
The small sample size and lack of specification of the intensity
of PE in the current pregnancy were among the limitations of
the present study. Herein, the efficacy of aspirin was evaluated
exclusively on the patients with a previous history of PE, which
is the strength of our study while there was no previous study
in which all the participants had a prior history of PE. However,
future studies are required with larger sample sizes to further
evaluate the efficacy of aspirin in women with a previous his-
tory of PE.
In conclusion, in the light of the present findings, it could be
concluded that taking aspirin is a preventive intervention for the
treatment of PE in pregnant women with at least a history of
one pregnancy afflicted with PE. However, in our study, the rate
of IUGR and preterm delivery did not change significantly after
taking aspirin.
ACKNOWLEDGMENTS
The present authors wish to be grateful to all who participated
in this research especially the esteemed professors and staff of
the maternity wards of Khalij Fars Hospital in Bandar Abbas.
The gratitude is extended to the research deputy of Hormozgan
University of Medical Sciences.
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Original Article. (2020) 83:9
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